The Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial is a large randomized trial to determine if screening for these cancers reduces mortality. The Trial is carried out by the NCI under contract with investigators at ten clinical centers in the United States. The study includes approximately 155,000 volunteers (recruited from 1993 through 2001, ages 55-74, equally distributed to the screening and control arms of the Trial). The PLCO Etiology and Early Markers Study (EEMS) supports etiologic and early detection studies of cancers and other conditions. EEMS uses data and samples collected in the context of the PLCO Trial including: 1. Baseline demographic and risk factor information on all participants, 2. Food Frequency Questionnaires(FFQ) on all participants 3. Fractionated blood specimens at each of six screening rounds from screened participants, 4. Buccal cell samples from control participants, and 5. Information on all-cancer incidence and selected other medical conditions. Investigations in PLCO EEMS have shown dietary-related factors associated with adenoma risk, including dietary fiber, meat cooking practices, serum selenium, low calcium intake, and a gene variant in the calcium-sensing receptor. Tobacco use was strongly related to adenoma risk, with evidence of risk modification by genes involved in the metabolism of PAH and aromatic amine constituents of tobacco smoke. Other factors associated with risk of colorectal adenoma included insulin-like growth factors and selected DNA repair-related polymorphisms. Prostate cancer risk was related to vegetable intake, particularly cruciferous vegetables, while dietary and serum lycopene were unrelated to risk. Supplemental vitamin E and serum alpha-tocopherol were related to risk only in smokers, consistent with other reports; serum selenium was also related to risk in smokers only. High-temperature cooked meat containing 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) led to increased risk, while only the highest levels of insulin-like growth factor-1 (IGF-1) were related to prostate cancer. Genetic studies of candidate genes in the PLCO Trial have revealed associations with SNPs in SHBG and risk of prostate cancer. Through the Breast and Prostate Cancer Cohort Consortium (BPC3) are evaluating prostate and breast cancer risks related to gene variants in steroid hormone and insulin-like growth factor pathways. Investigations in BPC3 and the Cancer Genetic Markers of Susceptibility (CGEMS) project are identifying prostate cancer risks associated with gene variants in the 8q24 region. Colon adenoma studies are now being expanded to consider the etiology of colon cancer, also in collaboration with other research groups. Studies of lymphoma and leukemia are in progress, and studies of bladder and endometrial cancer are being planned; efforts will expand as numbers of study subjects with a variety of cancers increase.